Professor of Emergency Medicine University of Massachusetts Shrewsbury, Massachusetts, United States
Chief Complaint: Mental status change
History of Present Illness: A 31-year-old male with a history of untreated depression and alcohol abuse was brought in by ambulance for somnolence after an intentional overdose on liquid Clonazolam that he had received from a friend. The patient had sent a suicidal text to his ex-girlfriend shortly before he ingested approximately half of a 3 ml bottle of liquid Clonazolam. When she arrived at his house, within approximately thirty minutes of his text, he appeared confused and intoxicated, so Emergency Medical Services (EMS) was called. Upon EMS arrival, the patient was somnolent. His fingerstick blood sugar was 108 mg/dL (normal range 70-100 mg/dL).
Pertinent Physical Exam: Afebrile, blood pressure 115/79 mm/Hg, heart rate 89, respiratory rate 22, and oxygen saturation of 94% on room air. The patient was somnolent and minimally following commands but was protecting his airway. Pupils were 4 mm, equal, round, and reactive to light. He was not diaphoretic. Lungs were clear and heart was regular rate and rhythm. Abdomen was soft and nontender. Bowel sounds were present. Patient had normal patellar reflexes without clonus. There were a few old, superficial abrasions to the left forearm. Glascow Coma Score was 12 (minus three for verbal response).
Pertinent Laboratory Data: Lab work was significant for a low normal bicarbonate of 22 mEq/L (normal range 22-29 mEq/L). The anion gap was normal. Potassium was slightly low at 3.2 mmol/L (normal range 3.6-5.2 mmol/L). Salicylate and acetaminophen levels were undetectable. Ethanol was 204 mg/dL. Urine drug screen (UDS) was positive for cocaine. It should be noted that benzodiazepines are not evaluated on our hospital’s UDS. EKG was non-ischemic with normal intervals.
Case
Discussion: Approximately one hour after arrival in the ED, the patient became somnolent with respiratory depression and oxygen saturations in the mid 80s. Flumazenil 0.2 mg intravenous (IV) was administered with immediate improvement in respiratory effort and oxygenation. One hour later, and additional 0.2 mg dose of IV flumazenil was again administered for respiratory depression and hypoxia. There were no Intensive Care Unit beds available, so the patient continued to board and be managed in the ED. Within six hours, his mental status normalized, and he was medically cleared for psychiatric evaluation.
Clonazolam (6-(2-chlorophenyl)-1-methyl-8-nitro 4H-triazolo[4,3-α] benzodiazepine is an analogue of clonazepam (1). It can be found in tablet, capsule, pellet, blotter, and liquid form, and can be purchased on the internet (2). Clonazolam is considered a designer benzodiazepine that has no medicinal indication. Since Clonazolam behaves similarly to benzodiazepines, it is likely safe to assume that it could be reversed by flumazenil, a benzodiazepine antagonist. Typical onset of action is one to two minutes with an 80% response rate within three minutes. Its peak effect is six to ten minutes with a duration of 19-50 minutes (3). There is currently a black box warning for flumazenil in the US as there has been a correlation with seizures, especially in patients on benzodiazepines long-term, and in those with severe tricyclic antidepressant overdose (4). Flumazenil is used more liberally in Europe.
Our patient ingested highly concentrated Clonazolam (approximately 7.5 mg) along with ethanol and cocaine. There is no regulated dose for Clonazolam, but profound sedation is thought to occur at doses of 0.5 mg (5). Cocaine may have counteracted some of the sedative effects of the Clonazolam. Reversal with flumazenil was chosen as opposed to intubation. This patient responded favorably to the flumazenil within the expected timeframe and had no resultant seizure activity.
References and Acknowledgements (Optional) 1. Hester JB, Rudzik AD, Kamdar BV. 6-phenyl-4H-s-triazolo[4,3-a] [1,4] benzodiazepines which have central nervous system depressant activity. J Med Chem. 1971;14(11):1078–1081. 2. Murphy L, Melamed J, Gerona R et al. (2019) Clonazolam: a novel liquid benzodiazepine, Toxicology Communications, 3:1, 75-78. 3. Sharbaf Shoar N, Bistas KG, Saadabadi A. Flumazenil. [Updated 2022 Aug 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. www.ncbi.nlm.nih.gov/books/NBK470180/ 4. Spivey WH. Flumazenil and seizures: analysis of 43 cases. Clin Ther. 1992 Mar-Apr;14(2):292-305. 5. Moosmann, B., & Auwärter, V. (2018). Designer benzodiazepines: another class of new psychoactive substances. In New psychoactive substances (pp. 383-410). Springer, Cham.
